The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on [3H]thymidine incorporation into hepatic DNA was studied in rats. In non-hepatectomized male and female animals, incorporation measured at the peak of the first round of liver DNA synthesis after TCDD treatment (10 micrograms/kg) was similar to that of control animals. In contrast, the first round of [3H]thymidine incorporation after a 1/3 hepatectomy was enhanced 3-fold in TCDD-treated rats. The enhanced response to 1/3 hepatectomy was produced by doses of TCDD ranging from 1 to 30 micrograms/kg with an apparent ED50 of 5 micrograms/kg. Enhanced incorporation was observed when the 1/3 hepatectomy was performed 5-10 days after an ED50 dose and it returned to the control level after 20 days. This enhanced response was not preceded by changes in food consumption or hepatic activities of ornithine decarboxylase (ODC), tyrosine aminotransferase (TAT) or gamma glutamyl transpeptidase (GGT) when compared to respective control values. Also, the enhanced incorporation was not necessarily due to removal of 1/3 of the liver because it was also seen in TCDD-treated rats that were laparotomized. The mechanism of enhancement in laparotomized animals does not appear to involve a diminished response of the liver to the inhibitory effects of adrenal hormones on liver DNA synthesis. This was suggested by the finding that an adrenalectomy prior to the laparotomy did not block the enhanced incorporation of [3H]thymidine into hepatic DNA. The mechanism by which TCDD enhances the first round of liver DNA synthesis after a 1/3 hepatectomy or laparotomy remains to be determined.